Anti-diabetic drug target perturbation modulates susceptibility to aortic aneurysm
Abstract
Background: Aortic aneurysms (AAs), including abdominal AA (AAA) and thoracic AA (TAA), are life-threatening conditions for which effective preventive therapies are lacking. Despite the promising results of anti-diabetic drugs in treating AAs, conclusive evidence supporting their efficacy remains lacking. Identifying effective anti-diabetic drugs for AAs is of considerable clinical importance.
Methods: Herein, we performed drug-target Mendelian randomisation (MR) using summary statistics from the largest genome-wide meta-analyses of AAA/TAA (FinnGen R10 and UK Biobank) and gene expression data from the eQTLGen consortium. Analyses included inverse-variance weighted MR, mediation MR (common risk factors), colocalisation, phenome-wide MR and animal experiment to validate causality and pleiotropy of the genes.
Results: Among the 10 anti-diabetic drug targets analysed, PRKAB1 (metformin target) showed protective effects against AAA (discovery OR = 0.92, 95 % CI: 0.88-0.97, P = 0.003; meta-OR = 0.93, 95 % CI: 0.89-0.97, P < 0.001) and TAA (discovery OR = 0.90, 95 % CI: 0.86-0.94, P < 0.001; meta-OR = 0.92, 95 % CI: 0.88-0.96, P = 0.002). Mediation MR demonstrated that 15.3 % (P = 0.021) and 11.7 % (P = 0.038) of the effects of PRKAB1 were mediated by elevated concentrations of high-density lipoprotein and reduced levels of triglycerides, respectively; insulin receptor reduced TAA risk (discovery OR = 0.86, 95 % CI: 0.75-0.99, P = 0.037; replication OR = 0.54, 95 % CI: 0.36-0.80,…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.